The present invention concerns an improved process for producing certain didehydro-dideoxynucleosides such as 2',3'-didehydro-3'-deoxythymidine (d4T) that is suitable for adaptation to large-scale manufacture.
There have been several processes reported for synthesizing 2',3'-didehydro-2',3'-dideoxynucleosides such as d4T. Most proceed via an anhydronucleosidic intermediate.
The nucleoside derivative, 2',3'-didehydro-3'-deoxythymidine (d4T), has previously been prepared by various synthetic processes. Horwitz et al, in Synthetic Procedures in Nucleic Acid Chemistry (Vol. 1), Zorbach et al (eds); Interscience, New York, p. 344, describe the process of Route 1 (below), which utilizes 3',5'-anhydrothymidine as the starting material, and employs flammable and moisture sensitive potassium tertiary butoxide (KOt-Bu) in dimethyl sulfoxide (DMSO). Besides the material handling difficulties, the process is impractical on a large scale due to decomposition of the product during its isolation from a DMSO solution, when it is subjected to the required high temperatures and strongly basic conditions for extended periods. ##STR1##
An improvement in isolation noted by Mansuri et al in J. Med. Chem., 1989, 461 (Route 2), gives the potassium salt of d4T as an oily solid by dilution of the DMSO reaction mixture with toluene before further processing. However, on a large scale, the volumes used are unmanageable and generate large amounts of waste solvents, which are difficult to recover. Also, the isolated salt is very sensitive to moisture and excessive drying. After redissolution and neutralization, crude d4T is isolated and dried and a further reslurry in solvent is necessary to obtain the final product. ##STR2##
Starrett, Jr. et al in U.S. Pat. No. 4,904,770 disclosed modification of the Mansuri process that comprised room temperature reaction of the 3',5'anhydro intermediate with the strong base in a polar organic solvent, e.g. KOt-Bu/DMSO followed by trituration of the resulting potassium salt of the 2',3'-didehydro-2',3'-dideoxynucleoside in an organic solvent, e.g. cold toluene. After redissolution and neutralization, crude d4T is obtained by acetone extraction of the solids isolated from the neutralization process.
A different approach to minimizing the product decomposition problem involved replacement of the KOt-Bu/DMSO system.
This variation (Route 3), using hexamethylphosphoric triamide (HMPA) and sodium hydroxide, eliminated the decomposition problems in the above Routes 1 and 2, since the HMPA solvent could be removed from an aqueous solution as a chloroform complex. However, the use of highly toxic agents that are reputed carcinogens as well, such as HMPA and chloroform, is hazardous on a large scale and is to be avoided. This process is disclosed in Adachi, et al, Carbohydrate Research, 1979, 113. ##STR3##
Cosford et al, in J. Org. Chem., 1991, 2161, disclose a less closely related route (Route 4) using a tritylated phenylselenyl thymidine derivative. The generation of highly toxic selenium wastes and the chromatography required are undesirable, especially on a large scale. ##STR4##